Since the first cases of acquired immunodeficiency syndrome (AIDS) were reported in 1981, infection with human immunodeficiency virus (HIV) has grown to pandemic proportions, resulting in an estimated 65 million infections and 25 million deaths. See Aug. 11, 2006, MMWR 55(31):841-844 (Center for Disease Control and Prevention). Protease inhibitors represent an important class of compounds used to treat individuals infected with HIV, although these compounds can also treat individuals suffering from other viral infections (e.g., Hepatitis C).
With respect to HIV, protease inhibitors act to inhibit the HIV viral proteases that are necessary for the proteolytic cleavage of the gag and gag/pol fusion polypeptides necessary for the generation of infective viral particles. Thus, by inhibiting this proteolytic cleavage, protease inhibitors diminish the ability of larger HIV-fusion polypeptide precursors to generate the mature form of protein necessary for effective viral replication. McQuade et al. (1990) Science 247(4941):454-456.
Protease inhibitor-based therapy is acknowledged as an initial treatment for patients presenting symptomatic HIV disease and in non-symptomatic patients after the CD4 cell count is below 350/μL but before a level of 200/μL. Hammer et al. (2006) JAMA 296(7):827-843. In such cases, a protease inhibitor-based regimen will include a protease inhibitor (typically boosted with ritonavir) along with a combination of two nucleoside (or nucleotide) reverse transcriptase inhibitors. Id.
These conventional HIV protease inhibitors, as well as other protease inhibitors, have relatively low potency and/or relatively low (or narrow) therapeutic index.
HIV and other protease inhibitors having a relatively high potency and/or relatively high (or wide) therapeutic index would represent an improvement over conventional HIV protease inhibitors.
Moreover, although protease inhibitors serve an important role in treating patients suffering from HIV as well as hepatitis viruses (e.g., hepatitis C virus), their use has been hampered by challenges associated with (among other things) limited oral bioavailability and lack of patient compliance due to the frequency of dosing and tolerability issues. Zeldin et al. (2004) J. Antimicrob. Chemother. 53:4-9. The lack of patient compliance, in turn, may lead to the development of resistant viral strains among patients treated with single PI regimens. Id.
In order to prevent or overcome resistance, concomitant administration with ritonavir—an inhibitor of cytochrome P-450 (CYP-450) and a protease inhibitor itself—has been used and has shown demonstrated efficacy in clinical studies. See Rathburn et al. (2002) Ann. Pharmacother. 36:702-706, Moyle et al. (2001) HIV Medicine 2:105-113, Flexner (2000) Ann. Rev. Pharm. Tox. 40:649-674, and Yu et al. (2000) Expert Opin. Pharmacother. 1:1331-1342. Interestingly, the dose of ritonavir administered in “boosted” protease inhibitor-based regimens is generally considered subtherapeutic. See Moyle et al. (2001) HIV Medicine 2:105-113.
Finally, sustained treatment with HIV protease inhibitors, however, has been found to lead to the generation of resistant HIV strains, which no longer respond to the protease inhibitor therapy. Such resistance is believed to be a consequence of mutations arising during viral replication that eventually lead to amino acid changes, which alter the binding interaction of the viral protease with the protease inhibitor and thus render the drug ineffective at preventing viral replication. In view of the chronic nature of HIV infection, the generation of resistant strains over the course of long-term therapy is particularly troubling.
The present disclosure seeks to address these and other needs in the art.